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Genetic Modulation of Senescent Phenotypes in Homo sapiens

2005; Cell Press; Volume: 120; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2005.01.031

1097-4172

George M. Martin,

DNA Repair Mechanisms

Single-gene mutations can produce human progeroid syndromes—phenotypes that mimic usual or “normative” aging. These can be divided into two classes—those that have their impacts upon multiple organs and tissues (segmental progeroid syndromes) and those that have their major impacts upon a single organ or tissue (unimodal progeroid syndromes). The prototypic example of the former is the Werner syndrome, a condition caused by mutations of the RecQ family of DNA helicases. Research on the Werner syndrome and a surprising number of other progeroid syndromes support the importance of the maintenance of genomic stability as a partial antidote to aging. The prototypic examples of the latter are Alzheimer type dementias. The three gene products that cause rare autosomal-dominant early-onset varieties of these disorders all participate in the modulation of the β amyloid precursor protein. They thus support the importance of the maintenance of proper protein processing and folding as a partial antidote to aging. Single-gene mutations can produce human progeroid syndromes—phenotypes that mimic usual or “normative” aging. These can be divided into two classes—those that have their impacts upon multiple organs and tissues (segmental progeroid syndromes) and those that have their major impacts upon a single organ or tissue (unimodal progeroid syndromes). The prototypic example of the former is the Werner syndrome, a condition caused by mutations of the RecQ family of DNA helicases. Research on the Werner syndrome and a surprising number of other progeroid syndromes support the importance of the maintenance of genomic stability as a partial antidote to aging. The prototypic examples of the latter are Alzheimer type dementias. The three gene products that cause rare autosomal-dominant early-onset varieties of these disorders all participate in the modulation of the β amyloid precursor protein. They thus support the importance of the maintenance of proper protein processing and folding as a partial antidote to aging. More is known about the range of variation of the anatomy, physiology, biochemistry, nutrition, microbiology, immunology, pathology, pharmacology, behavior, and demography of Homo sapiens than any other animal species on earth. Until about the last decade or so, the missing ingredient was the formal genetic analysis of our species, including a comprehensive catalog of allelic variants. Progress in that direction has been spectacular, providing unprecedented opportunities for the detailed biochemical genetic characterizations of individuals with unusually well-preserved or unusually fragile functions during the life course. Moreover, given our propensity to colonize virtually every segment of the globe there are almost unlimited opportunities to uncover novel nature-nature interactions. This review focuses upon rare mutations that appear to accelerate the ages of onset and/or the rates of progression of degenerative and proliferative disorders that mimic, with varying degrees of fidelity, what the physician and pathologist would characterize as senescent phenotypes. Every gerontologist would agree that a much more informative approach would be to focus upon the genetic basis of unusually well-preserved structure and function. There are many ways to damage a machine, most of them probably differing from what drives aging as it unfolds in most individuals. There are comparatively few ways, however, to make the machine work better for longer periods of time. Although there have been some recent attempts to uncover alleles associated with unusual longevities (Barzilai et al., 2003Barzilai N. Atzmon G. Schechter C. Schaefer E.J. Cupples A.L. Lipton R. Cheng S. Shuldiner A.R. Unique lipoprotein phenotype and genotype associated with exceptional longevity.JAMA. 2003; 290: 2030-2040Crossref PubMed Scopus (461) Google Scholar), progress has been limited by a paucity of data on rates of change in a wide range of physiological functions using highly sensitive and relatively noninvasive methods that are amenable to longitudinal studies in very large populations of middle-aged subjects (Martin, 2002aMartin G.M. Help wanted: physiologists for research on aging.Sci. Aging Knowledge Environ. 2002; 9: vp2Google Scholar). Given such data, genetic methods such as sib-pair analysis (Szatkiewicz and Feingold, 2004Szatkiewicz J.P. Feingold E. A powerful and robust new linkage statistic for discordant sibling pairs.Am. J. Hum. Genet. 2004; 75: 906-909Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar) have the potential to uncover subsets of alleles that modulate aging as it usually unfolds, at least for those phenotypes that are not modulated by hundreds of alleles with very small effects. But this is a review that must await a decade or more of progress. Meanwhile we have to make the most of what we can from reports of deleterious mutations. Fortunately, there is a strong rationale for this approach—namely that for every allele that codes for a defective protein or suboptimum regulation, there can exist, in principle, alleles with functions superior to those of wild-type, including alleles that provide enhanced functions late in the life course. This is predicted by the evolutionary theory of aging, as “good” alleles as well as “bad” alleles can escape the force of natural selection (Martin, 2002bMartin G.M. The evolutionary substrate of aging.Arch. Neurol. 2002; 59: 1702-1705Crossref PubMed Scopus (11) Google Scholar). In short, the discovery of genes that lead to unsuccessful aging can lead us to the discovery of variants that can lead to unusually successful aging. It is convenient to classify genetic syndromes that mimic senescent features into two broad categories—those that impact upon a suite of such features involving a number of organ systems and tissues and those that have a predominant impact only upon a single organ system or tissue. I have referred to the former as “segmental progeroid syndromes” (Martin, 1978Martin G.M. Genetic syndromes in man with potential relevance to the pathobiology of aging.Birth Defects Orig. Artic. Ser. 1978; 14: 5-39PubMed Google Scholar) and the latter as “unimodal progeroid syndromes” (Martin, 1982Martin, G.M. (1982). Syndromes of accelerated aging. International Symposium: Research Frontiers in Aging and Cancer 60, 241–247.Google Scholar). In this review, we shall focus upon those entities for which a single gene or genes have been identified as the underlying primary event. Not all of these are reviewed, given the potentially very large number of these disorders and the lack of more precise information on the degrees of concordance and discordance with senescent phenotypes as they usually occur in the general population. Given the fact that we are still largely ignorant of the range of mechanisms responsible for senescent phenotypes as they usually unfold in different individuals, it is prudent to use the term “progeroid syndrome” rather than “premature aging syndrome.” The suffix “-oid” means “like.” It does not imply that the phenotypes or their underlying mechanisms exactly duplicate usual or “normative” aging. The latter themselves are likely to be mechanistically heterogeneous. This author embraces the evolutionary theory of aging, which does not predict determinative, sequential changes in gene action that lead to highly reproducible phenotypes. (Indeed, every physician will note that patterns of aging are highly variable among geriatric patients.) While the discovery of a “public mechanism of aging” in C. elegans, Drosophila melanogaster, and Mus musculus domesticus is of great importance (Partridge and Gems, 2002Partridge L. Gems D. Mechanisms of ageing: public or private?.Nat. Rev. Genet. 2002; 3: 165-175Crossref PubMed Scopus (390) Google Scholar), the leaky mutations that formed the basis for these discoveries can be interpreted as reporting on genetic pathways that evolved to maintain a high degree of somatic maintenance under harsh environmental conditions that trigger transient withdrawal from the business of reproduction. There are numerous examples of such “diapauses” in nature, particularly in insects (Brown and Hodek, 1983Brown V.K. Hodek I. Diapause and Life Cycle Strategies in Insects. Junk, The Hague1983Google Scholar); caloric restriction may well be another diapausal mechanism that evolved within numerous phyla. These mechanisms of survival are eventually trumped by a variety of gene actions that escape the force of natural selection (Martin, 2002bMartin G.M. The evolutionary substrate of aging.Arch. Neurol. 2002; 59: 1702-1705Crossref PubMed Scopus (11) Google Scholar). This is the prototypic segmental progeroid syndrome because it impacts upon a very large number of senescent phenotypes of major medical importance (Goto et al., 2001Goto M. Miller R.W. Nihon G.G. From Premature Gray Hair to Helicase–Werner Syndrome Implications for Aging and Cancer. Japan Scientific Societies Press, Tokyo2001Google Scholar). In typical cases there is no clinical evidence of an abnormality until puberty, when the affected subject fails to demonstrate an adolescent growth spurt. The result is short stature as an adult (but not as a schoolchild). Other features (see Figure 1) include bilateral ocular cataracts; a characteristic set of dermatological signs (atrophic, “tight” skin, reminiscent of scleroderma, pigmentary abnormalities, premature graying and/or thinning of scalp hair, striking loss of peripheral subcutaneous tissue, skin ulcerations [including virtually pathognomonic ulcerations around the malleoli and Achilles tendons], subcutaneous and peri-articular deposits of calcium [Leone et al., 2005Leone A. Costantini A.M. Brigida R. Antoniol O.M. Antonelli-Incalzi R. Bonomo L. Soft-tissue mineralization in Werner syndrome.Skeletal Radiol. 2005; 34: 47-51Crossref PubMed Scopus (17) Google Scholar], and a “bird-like,” “pinched” facie); osteoporosis (particularly of the long bones of the legs); radiologically characteristic osteosclerosis of the distal phalanges; hypogonadism; several types of arteriosclerosis; a history of myocardial infarction and, less frequently, the effects of cerebral ischemia; severe calcifications of heart valves; variable evidence of type 2 diabetes mellitus; peripheral neuropathy; benign and malignant neoplasia, predominately of nonepithelial origins and including high frequencies of rare cancers (Goto et al., 1996Goto M. Miller R.W. Ishikawa Y. Sugano H. Excess of rare cancers in Werner syndrome (adult progeria).Cancer Epidemiol. Biomarkers Prev. 1996; 5: 239-246PubMed Google Scholar). Multiple distinct primary neoplasms can occur—as many as five malignancies in one patient (Tsuchiya et al., 1991Tsuchiya H. Tomita K. Ohno M. Inaoki M. Kawashima A. Werner's syndrome combined with quintuplicate malignant tumors: a case report and review of literature data.Jpn. J. Clin. Oncol. 1991; 21: 135-142PubMed Google Scholar). The two major causes of death (at a median age of around 47–48 years) are myocardial infarctions and cancer. A family history frequently reveals parental consanguinity, as one would expect for a rare autosomal recessive condition. Experienced geriatricians will note a number of important discordances between the above phenotype and what is typically observed in “normative” aging—for example, the pattern of neoplasms and the distribution of the osteoporosis. Early work with cultured somatic cells from Werner patients documented accelerated clonal senescence, a mosaic of chromosomal translocations, deletions, and inversions, and elevated frequencies of somatic mutations, particularly deletions. Positional cloning led to the identification of the mutant locus as a member of the RecQ family of helicases. Affected patients are homozygous or doubly heterozygous for null mutations associated with truncated gene products missing their nuclear localization signals. The WRN helicase is unusual in that it is the only one of five members of the human family that includes an exonuclease domain. Claims have been made for the functioning of the WRN helicase in a variety of DNA transactions, including DNA replication (Sharma et al., 2004Sharma S. Sommers J.A. Brosh Jr., R.M. In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication.Hum. Mol. Genet. 2004; 13: 2247-2261Crossref PubMed Scopus (44) Google Scholar), homologous recombination (Monnat and Saintigny, 2004Monnat Jr., R.J. Saintigny Y. Werner syndrome protein–unwinding function to explain disease.Sci. Aging Knowledge Environ. 2004; 13: re3Google Scholar), nonhomologous end joining (Oshima et al., 2002Oshima J. Huang S. Pae C. Campisi J. Schiestl R.H. Lack of WRN results in extensive deletion at nonhomologous joining ends.Cancer Res. 2002; 62: 547-551PubMed Google Scholar), base excision repair (Ahn et al., 2004Ahn B. Harrigan J.A. Indig F.E. Wilson III, D.M. Bohr V.A. Regulation of WRN helicase activity in human base excision repair.J. Biol. Chem. 2004; 279: 53465-53474Crossref PubMed Scopus (71) Google Scholar), and transcription (Balajee et al., 1999Balajee A.S. Machwe A. May A. Gray M.D. Oshima J. Martin G.M. Nehlin J.O. Brosh R. Orren D.K. Bohr V.A. The Werner syndrome protein is involved in RNA polymerase II transcription.Mol. Biol. Cell. 1999; 10: 2655-2668Crossref PubMed Scopus (116) Google Scholar). It is likely to have a role in a number of pathways dealing with the resolution of unusual DNA substrates, including, probably of considerable importance, telomere sequences. The latter assertion is supported by at least four lines of evidence. The first is the fact that transfection of Werner cells with the catalytic subunit of telomerase bypasses the premature replicative senescence (Wyllie et al., 2000Wyllie F.S. Jones C.J. Skinner J.W. Haughton M.F. Wallis C. Wynford-Thomas D. Faragher R.G. Kipling D. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.Nat. Genet. 2000; 24: 16-17Crossref PubMed Scopus (278) Google Scholar). The second is the ability of trisubstituted acridine ligands that interact with G-quadriplex DNA structures to inhibit the Werner helicase (Li et al., 2001Li J.L. Harrison R.J. Reszka A.P. Brosh Jr., R.M. Bohr V.A. Neidle S. Hickson I.D. Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands.Biochemistry. 2001; 40: 15194-15202Crossref PubMed Scopus (95) Google Scholar). The third is the observation that a knockout of telomerase function in mice, after several generations of breeding, reduces the unusually long telomere murine sequences to sizes characteristic of what is observed in the somatic cells of human subjects. Such “humanization” revealed a variety of phenotypes characteristic of the Werner syndrome (Chang et al., 2004Chang S. Multani A.S. Cabrera N.G. Naylor M.L. Laud P. Lombard D. Pathak S. Guarente L. DePinho R.A. Essential role of limiting telomeres in the pathogenesis of Werner syndrome.Nat. Genet. 2004; 36: 877-882Crossref PubMed Scopus (360) Google Scholar, Du et al., 2004Du X. Shen J. Kugan N. Furth E.E. Lombard D.B. Cheung C. Pak S. Luo G. Pignolo R.J. DePinho R.A. et al.Telomere shortening exposes functions for the mouse werner and bloom syndrome genes.Mol. Cell. Biol. 2004; 24: 8437-8446Crossref PubMed Scopus (178) Google Scholar). The fourth and most recent observation is a role for the Werner helicase in telomere lagging strand synthesis (Crabbe et al., 2004Crabbe L. Verdun R.E. Haggblom C.I. Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.Science. 2004; 306: 1951-1953Crossref PubMed Scopus (465) Google Scholar). Approximately 10% of cases of apparent Werner syndrome have somewhat atypical clinical features and fail to reveal mutations at the WRN locus or deficiencies in the WRN protein. A few of these cases were shown to be due to mutations at the LMNA/C locus, but at domains upstream from the common mutation responsible for the classical form of the Hutchinson-Gilford syndrome (see below) (Chen et al., 2003Chen L. Lee L. Kudlow B.A. Dos Santos H.G. Sletvold O. Shafeghati Y. Botha E.G. Garg A. Hanson N.B. Martin G.M. et al.LMNA mutations in atypical Werner's syndrome.Lancet. 2003; 362: 440-445Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). Candidate genes for other forms of “Atypical Werner Syndrome” would certainly include the growing list of proteins that interact with the Werner helicase; of particular interest would be members of the complex of proteins that participate in the resolution of stalled DNA replication forks (Robison et al., 2004Robison J.G. Elliott J. Dixon K. Oakley G.G. Replication protein A and the Mre11.Rad50.Nbs1 complex co-localize and interact at sites of stalled replication forks.J. Biol. Chem. 2004; 279: 34802-34810Crossref PubMed Scopus (118) Google Scholar). Research on the detailed molecular biology of gene actions at WRN and other RecQ loci (notably at the BLM locus, mutations at which are associated with an array of neoplasms quite comparable with what is observed in usual aging) is at a stage of rapid development. We would especially like to know the potential impacts of more subtle deficiencies of these gene actions, including those related to the numerous proteins that interact with these helicases to make these marvelous “molecular motors.” Only a few papers have appeared concerning the impact of WRN polymorphisms and WRN haploinsufficiency upon senescent phenotypes and life span; the data remain insufficient to warrant any definitive conclusions. This is unfortunate, given the possibility that these much more prevalent variants could impact upon substantially larger populations. The Werner syndrome has already helped to clarify some important issues in biogerontology, however. First, it provides strong support for the notion that genomic instability is important for a variety of senescent phenotypes. This is reinforced by studies of other putative progeroid syndromes. Second, it supports the proposition that replicative senescence contributes to various senescent phenotypes. Third, it supports the proposition that mesenchymal tissues play major roles in the modulation of senescent phenotypes since mesenchymal cell types appear to be especially vulnerable targets and are disproportionately represented in the spectrum of neoplasms observed in that disorder. Fourth, it raises the question that DNA crosslinking agents may have progeroid effects, as somatic cells from Werner patients appear to be particularly susceptible to drugs that induce DNA interstrand crosslinks (Poot et al., 2001Poot M. Yom J.S. Whang S.H. Kato J.T. Gollahon K.A. Rabinovitch P.S. Werner syndrome cells are sensitive to DNA cross-linking drugs.FASEB J. 2001; 15: 1224-1226Crossref PubMed Scopus (131) Google Scholar). The old literature referred to this exceedingly rare condition (∼1/8 million births) as “Childhood Progeria” in order to differentiate it from the Werner syndrome, which is sometimes referred to as “Adult Progeria.” A skilled pediatrician can make the diagnosis within the first few months of life and certainly by the end of the first year of life (DeBusk, 1972DeBusk F.L. The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature.J. Pediatr. 1972; 80: 697-724Abstract Full Text PDF PubMed Scopus (278) Google Scholar, Brown, 2003Brown W.T. Hutchinson-Gilford Progeria Syndrome.in: Hisami F.M. Weissman S.M. Martin G.M. Chromosomal Instability and Aging Basic Science and Clinical Implications. Marcel Dekker, New York2003: 245-261Google Scholar). The disorder thus clearly impacts upon normal development and thus one can question the appropriateness of the designation as a Progeria (literally, “premature aging”). Its striking features include severe retardation of growth and marked loss of subcutaneous fat, particularly of the face and limbs, giving the characteristic “bird-like” facies and the facile mapping of the veins of the scalp. Skin appendages disappear, including eye lashes and eyebrows. Like the Werner syndrome, the voice is weak, high pitched, or squeaky. Clavicles may consist only of connective tissue, without developed cartilage. The connective tissue abnormalities can lead to dislocated hips and the characteristic “horse-riding” stance; the result can be a form of osteoarthritis. Like Werner syndrome patients, abnormalities of the distal phalanges are seen by X-ray. Also like the Werner syndrome, there is no evidence of any cognitive impairment in the absence of any complications of arteriosclerosis. The latter, particularly atherosclerosis, is the most compelling feature from the point of view of the gerontologist, many of whom would regard it as a characteristic feature of aging in our species, although with substantial variations in rates of development as functions of the background genome and the environment (Eggen and Solberg, 1968Eggen D.A. Solberg L.A. Variation of atherosclerosis with age.Lab. Invest. 1968; 18: 571-579PubMed Google Scholar). Atherosclerosis is certainly an example of a phenotype that almost always escapes the force of natural selection in human populations and therefore might reasonably be regarded as a senescent phenotype. For Hutchinson-Gilford patients, however, it may result in myocardial infarction and death at around the age of 13; such virulent mutations are therefore under strong selective pressure. The histology of atherosclerotic arteries require much more study, but the evidence suggests only subtle differences from the type of atherosclerosis one observes in the population at large; one study suggested that the arteries are more susceptible to mechanical damage (Stehbens et al., 1999Stehbens W.E. Wakefield S.J. Gilbert-Barness E. Olson R.E. Ackerman J. Histological and ultrastructural features of atherosclerosis in progeria.Cardiovasc. Pathol. 1999; 8: 29-39Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar)—a prescient observation, considering the subsequent elucidation of the nature of the abnormal gene products. Those gene products turned out to be structural components of the nuclear membrane (Lamins A and C) (Goldman et al., 2004Goldman R.D. Shumaker D.K. Erdos M.R. Eriksson M. Goldman A.E. Gordon L.B. Gruenbaum Y. Khuon S. Mendez M. Varga R. Collins F.S. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome.Proc. Natl. Acad. Sci. USA. 2004; 101: 8963-8968Crossref PubMed Scopus (749) Google Scholar). About 90% of the classical cases so far investigated result from dominant de novo germline mutations involving a C to T transition (Eriksson et al., 2003Eriksson M. Brown W.T. Gordon L.B. Glynn M.W. Singer J. Scott L. Erdos M.R. Robbins C.M. Moses T.Y. Berglund P. et al.Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature. 2003; 423: 293-298Crossref PubMed Scopus (1476) Google Scholar). The new codon continues to code for glycine but results in a splicing abnormality such that an abnormal lamin A is synthesized that is missing 50 amino acids near the C-terminal end of the molecule (Eriksson et al., 2003Eriksson M. Brown W.T. Gordon L.B. Glynn M.W. Singer J. Scott L. Erdos M.R. Robbins C.M. Moses T.Y. Berglund P. et al.Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature. 2003; 423: 293-298Crossref PubMed Scopus (1476) Google Scholar). Nuclear lamins are members of a family of intermediate filament proteins. Lamins A and C are among at least four gene products derived from the single lamin A/C locus via differential splicing. They have multiple roles, still poorly defined, associated with their localizations on the inner nuclear envelope and as a fibrillar web throughout the nucleoplasm. These can be presumed to include nuclear structural and regulatory interactions with chromatin. Tissues undergoing mechanical stresses are particularly vulnerable to lamin A/C mutations (Worman and Courvalin, 2004Worman H.J. Courvalin J.C. How do mutations in lamins A and C cause disease?.J. Clin. Invest. 2004; 113: 349-351Crossref PubMed Scopus (116) Google Scholar). The Hutchinson-Gilford syndrome may therefore influence research on the pathogenesis of atherosclerosis as it usually occurs. Perhaps the primary lesion is a reaction of smooth muscle and/or endothelial cells to arterial injury such as those associated with hypertension or with alterations in blood flow at arterial bifurcations. Inflammatory responses, including infiltrations by macrophages and depositions of cholesterol and oxidized lipoproteins, might therefore be downstream processes. It is also possible that accelerated clonal, replicative senescence of cells of the vascular wall sets the stage for the subsequent atherosclerotic events, not only in the Werner and Hutchinson-Gilford syndromes, but perhaps also in most forms of atherosclerosis (Martin and Sprague, 1972Martin G.M. Sprague C.A. Clonal senescence and atherosclerosis.Lancet. 1972; 2: 1370-1371Abstract PubMed Scopus (14) Google Scholar). Patients affected by this autosomal recessive disorder exhibit progressive cerebellar degeneration, particularly of Purkinje cells, a spectrum of immunodeficiency markers with resulting susceptibility to infections (especially otitis media, sinusitis, and bronchopneumonia), hypogonadism, a variety of degenerative and proliferative lesions of the skin and skin appendages (telangiectasia, atrophy, pigmentary abnormalities, graying of hair, senile keratosis), and a wide range of malignant neoplasms, with non-Hodgkin’s lymphomas being particularly frequent (reviewed by Meys, 2003Meys M.S. Ataxia-Telangiectasia.in: Hisami F.M. Weissman S.M. Martin G.M. Chromosomal Instability and Aging. Marcel Dekker, Inc., New York2003: 263-309Google Scholar). These patients are hypersensitive to ionizing irradiation, so that radiation treatment for neoplasia is problematic. Affected patients are homozygous or doubly heterozygous for a range of mutations leading to a deficiency of an unusually large protein kinase that is at a nodal position in a signaling cascade that comes into play when there are double-strand breaks in DNA, such as those produced by ionizing radiation (reviewed by McKinnon, 2004McKinnon P.J. ATM and ataxia telangiectasia.EMBO Rep. 2004; 5: 772-776Crossref PubMed Scopus (266) Google Scholar). These include physiological double-strand breaks such as those that occur during meiosis and during recombination associated with the maturation of the immune system, thus explaining features of the pathology. There is evidence that the kinase is responding to endogenous oxidative stress (Reichenbach et al., 2002Reichenbach J. Schubert R. Schindler D. Muller K. Bohles H. Zielen S. Elevated oxidative stress in patients with ataxia telangiectasia.Antioxid. Redox Signal. 2002; 4: 465-469Crossref PubMed Scopus (138) Google Scholar). The insulin-like growth factor-1 receptor is among the downstream target genes regulated by the ATM kinase (Shahrabani-Gargir et al., 2004Shahrabani-Gargir L. Pandita T.K. Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1.Endocrinology. 2004; 145: 5679-5687Crossref PubMed Scopus (49) Google Scholar). This should be of considerable interest to gerontologists, given the evidence that the IGF-1 pathway has been the first metabolic network implicated as a “public” modulation of rates of aging (Partridge and Gems, 2002Partridge L. Gems D. Mechanisms of ageing: public or private?.Nat. Rev. Genet. 2002; 3: 165-175Crossref PubMed Scopus (390) Google Scholar). In the presence of DNA damage, ATM directly regulates CREB, a transcription factor important for neuronal homeostasis and survival (Shi et al., 2004Shi Y. Venkataraman S.L. Dodson G.E. Mabb A.M. LeBlanc S. Tibbetts R.S. Direct regulation of CREB transcriptional activity by ATM in response to genotoxic stress.Proc. Natl. Acad. Sci. USA. 2004; 101: 5898-5903Crossref PubMed Scopus (81) Google Scholar); this may provide an important clue for the basis of the neurodegenerative phenotypes, although the unusual susceptibility of the cerebellar cortex will have to be explained. Neurologists have long noted a remarkable variability of age of onset of the cerebellar degenerative signs of the disease, often leading to considerable uncertainty concerning the diagnosis. We now know that unusually late onset of the disorder can be explained by leaky mutations (Dork et al., 2004; Sutton et al., 2004Sutton I.J. Last J.I. Ritchie S.J. Harrington H.J. Byrd P.J. Taylor A.M. Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity.Ann. Neurol. 2004; 55: 891-895Crossref PubMed Scopus (40) Google Scholar). The lesson a gerontologist takes from these disorders is that gain-of-function nontranslated RNA transcripts from a locus with expanded simple repeat units can produce transdominant splicing abnormalities at other loci, resulting in numerous degenerative adult-onset disorders (e.g., muscle weakness and atrophy, bilateral ocular cataracts, type 2 diabetes mellitus, cardiomyopathy, testicular atrophy, immune deficiency) (reviewed by Ranum and Day, 2004Ranum L.P. Day J.W. Myotonic dystrophy: RNA pathogenesis comes into focus.Am. J. Hum. Genet. 2004; 74: 793-804Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). Although DM1 can be associated with neuropsychiatric abnormalities and may be expressed much earlier, all other clinical features are found in both forms of the disease, even though the repeat units and the genetic loci are distinct. (The expanded DM1 triplet repeat is on chromosome 19 w